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Ludwig Institute for Cancer Research, Uppsala University, Box 595 Biomedical Center, SE-751 24 Uppsala, Sweden

Correspondence to Aristidis Moustakas: aris.moustakas{at}licr.uu.se

Signal transduction by transforming growth factor β (TGFβ) coordinates physiological responses in diverse cell types. TGFβ signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFβ signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFβ/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFβ. We thus identify in SIK a negative regulator that controls TGFβ receptor turnover and physiological signaling.

M. and K. Kowanetz's current address is Genentech, Inc., South San Francisco, CA 94080.

Abbreviations used in this paper: ALK, activin receptor-like kinase; BMP, bone morphogenetic protein; CA, constitutively active; GAPDH, glyceraldehyde-3'-phosphate dehydrogenase; PAI-1, plasminogen activator inhibitor 1; SIK, salt-inducible kinase; TβRII, TGFβ type II receptor; TCL, total cell lysate; UBA, ubiquitin associated.

© 2008 Kowanetz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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